This information is intended for use by health professionals

1. Name of the medicinal product

Migramax 900 mg/10 mg Powder for oral solution

2. Qualitative and quantitative composition

Active ingredients

Per sachet

DL-lysine acetylsalicylate

1,620mg

equivalent to acetylsalicylic acid

900mg

Metoclopramide (INN) hydrochloride EP

10.54mg

equivalent in terms of the anhydrous substance to:

10mg

3. Pharmaceutical form

Sachet containing powder for oral solution

4. Clinical particulars
4.1 Therapeutic indications

Adult population

MigraMax is indicated for the treatment of migraine-associated symptoms such as headache, nausea and vomiting.

4.2 Posology and method of administration

For oral administration only.

MigraMax must be dissolved completely in some water before taking.

Adults (aged 18 years and older)

One sachet should be taken at the first warning of a migraine attack. A second sachet may be taken two hours later if the symptoms have not resolved. Do not exceed three sachets in a 24 hour period.

Elderly

In elderly patients a dose reduction should be considered, based on renal and hepatic function and overall frailty.

Renal impairment

In patients with end stage renal disease (Creatinine clearance ≤ 15 ml/min), the daily dose should be reduced by 75%.

In patients with moderate to severe renal impairment (Creatinine clearance 15-60 ml/min), the dose should be reduced by 50% (see section 5.2).

Hepatic impairment

In patients with severe hepatic impairment, the dose should be reduced by 50% (see section 5.2).

Paediatric population including adolescents

Metoclopramide is contraindicated in children aged less than 1 year (see section 4.3).

Use in children and adolescents between the ages of 1 and 18 years is not recommended.

Treatment should not exceed 3 months due to the presence of metoclopramide (see sections 4.4 and 4.8)

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• Patients with pre-existing mastocytosis, in whom the use of acetylsalicyclic acid may induce severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia and vomiting). In these patients, aspirin has the potential to induce anaphylaxis either on its own or in combination with food and/or exercise.

• Gastrointestinal haemorrhage, mechanical obstruction or gastro-intestinal perforation for which the , stimulation of gastrointestinal motility constitutes a risk

• Confirmed or suspected pheochromocytoma, due to the risk of severe hypotension episodes

• History of neuroleptic or metoclopramide-induced tardive dyskinesia.

• Epilepsy (increased crisis frequency and intensity)

• Parkinson's disease.

• Combination with levodopa or dopaminergic agonists (see section 4.5)

• Known history of methaemoglobinaemia with metoclopramide or of NADH cytochrome- b5 deficiency.

• Active, chronic or recurrent gastric or duodenal ulcers.

• Congenital or acquired bleeding disorders; obstruction, haemorrhage or perforation of the GI tract.

• Third trimester of pregnancy.

• Metoclopramide should not be used in the immediate post-operative period (up to 3-4 days) following pyloroplasty or gut anastomosis, as vigorous gastro-intestinal contractions may adversely affect healing.

• Patients with severe hepatic insufficiency

• Patients with severe renal insufficiency (CrCL <30 ml/min)

• Use in children less than 1 year of age due to increased risk of extrapyramidal disorders (see section 4.4)

4.4 Special warnings and precautions for use

If vomiting persists the patient should be reassessed to exclude the possibility of an underlying disorder e.g. cerebral irritation.

As salicylates may induce asthma attacks in susceptible individuals MigraMax should be avoided in patients at risk of developing sensitivity reactions. These include individuals with asthma or rhinitis, a history of atopy or nasal polyps, and also patients who have been sensitive to other salicylates or NSAIDs.

Use with caution in patients with a history of gastroduodenal ulcer or GI haemorrhage, or with mild and moderate hepatic impairment, gout, menorrhagia, or epilepsy. Care should be taken in patients using intra-uterine contraceptive devices and patients who have a high alcohol intake.

There is a possible association between aspirin and Reye's syndrome when given to children. Reye's syndrome is a very rare disease which affects the brain and liver, and can be fatal. For this reason aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).

MigraMax is contraindicated in patients under 18 years of age.

As total clearance of metoclopramide is reduced and elimination prolonged in patients with renal failure use in patients with significant degrees of renal impairment should be approached with caution.

Metoclopramide may induce an acute hypertensive response in patients with phaeochromocytoma.

Due to the risk of tardive dyskinesia with metoclopramide, treatment should not exceed 3 months (see also sections 4.2 and 4.8).

Neurological disorders

Extrapyramidal disorders may occur, particularly in children and young adults, and/or when high doses are used. These reactions occur usually at the beginning of the treatment and can occur after a single administration. Metoclopramide should be discontinued immediately in the event of extrapyramidal symptoms. These effects are generally completely reversible after treatment discontinuation, but may require a symptomatic treatment (benzodiazepines in children and/or anticholinergic anti-Parkinsonian medicinal products in adults). The time interval of at least 6 hours specified in the section 4.2 should be respected between each metoclopramide administration, even in case of vomiting and rejection of the dose, in order to avoid overdose.

Prolonged treatment with metoclopramide may cause tardive dyskinesia, potentially irreversible, especially in the elderly. Treatment should not exceed 3 months because of the risk of tardive dyskinesia (see section 4.8). Treatment must be discontinued if clinical signs of tardive dyskinesia appear.

Metoclopramide is not recommended in epileptic patients as benzamides may decrease the epileptic threshold.

Neuroleptic malignant syndrome has been reported with metoclopramide in combination with neuroleptics as well as with metoclopramide monotherapy (see section 4.8). Metoclopramide should be discontinued immediately in the event of symptoms of neuroleptic malignant syndrome and appropriate treatment should be initiated.

The management of NMS should include:

1) immediate discontinuation of the product,

2) intensive symptomatic treatment and medical monitoring and

3) treatment of any concomitant serious medical problems for which specific treatments are available.

Special care should be exercised in patients with underlying neurological conditions and in patients being treated with other centrally-acting drugs (see section 4.3).

Symptoms of Parkinson's disease may also be exacerbated by metoclopramide.

Methaemoglobinaemia

Methemoglobinemia which could be related to NADH cytochrome b5 reductase deficiency has been reported. In such cases, metoclopramide should be immediately and permanently discontinued and appropriate measures initiated (such as treatment with methylene blue).

Cardiac disorders

There have been reports of serious cardiovascular undesirable effects including cases of circulatory collapse, severe bradycardia, cardiac arrest and QT prolongation following administration of metoclopramide by injection, particularly via the intravenous route (see section 4.8).

Special care should be taken when administering metoclopramide, particularly via the intravenous route to the elderly population, to patients with cardiac conduction disturbances (including QT prolongation), patients with uncorrected electrolyte imbalance, bradycardia and those taking other drugs known to prolong QT interval.

Intravenous doses should be administered as a slow bolus (at least over 3 minutes) in order to reduce the risk of adverse effects (e.g. hypotension, akathisia).

Renal and hepatic impairment

In patients with renal impairment or with severe hepatic impairment, a dose reduction is recommended (see section 4.2).

Care should be exercised when using MIGAMAX SACHETS in patients with a history of atopy (including asthma) or porphyria.

For acetylsalicylic acid > 500mg/day:

There is some evidence that drugs which inhibit cyclo-oxygenase / prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

This drug must be administered under close medical supervision in patients with glucose-6 phosphate dehydrogenase deficiency due to risk of haemolysis (see section 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

Metoclopramide

Contraindicated combination

Levodopa or dopaminergic agonists and metoclopramide have a mutual antagonism (see section 4.3).

Combination to be avoided

Alcohol potentiates the sedative effect of metoclopramide.

Combinations to be taken into account

Due to the prokinetic effect of metoclopramide, the absorption of certain drugs may be modified.

Anticholinergics and morphine derivatives

Anticholinergics and morphine derivatives may have both a mutual antagonism with metoclopramide on the digestive tract motility.

Central nervous system depressants (morphine derivatives, anxiolytics, sedative H1 antihistamines, sedative antidepressants, barbiturates, clonidine and related)

Sedative effects of Central Nervous System depressants and metoclopramide are potentiated.

Neuroleptics

Metoclopramide may have an additive effect with other neuroleptics on the occurrence of extrapyramidal disorders.

Serotonergic drugs

The use of metoclopramide with serotonergic drugs such as SSRIs may increase the risk of serotonin syndrome.

Digoxin

Metoclopramide may decrease digoxin bioavailability. Careful monitoring of digoxin plasma concentration is required.

Ciclosporin

Metoclopramide increases ciclosporin bioavailability (Cmax by 46% and exposure by 22%). Careful monitoring of ciclosporin plasma concentration is required. The clinical consequence is uncertain.

Mivacurium and suxamethonium

Metoclopramide injection may prolong the duration of neuromuscular block (through inhibition of plasma cholinesterase).

Strong CYP2D6 inhibitors

Metoclopramide exposure levels are increased when co-administered with strong CYP2D6 inhibitors such as fluoxetine and paroxetine. Although the clinical significance is uncertain, patients should be monitored for adverse reactions

Alcohol

Alcohol potentiates the sedative effect of metoclopramide

Antipsychotics

Combination of antipsychotics with metoclopramide may result in potentiation of extrapyramidal effects.

Salicylate-related interactions

Anti-coagulants

Salicylates may enhance the effects of anti-coagulants.

Oral anti-diabetic agents

Salicylates may enhance the effects of oral anti-diabetic agents.

Anti-epileptics

Salicylates may enhance the effects of phenytoin, sodium valproate.

Antimetabolites

Salicylates may enhance the effects of methotrexate

Immunomodulating agents

Salicylates may inhibit the action of alpha interferon

Salicylates may interact with other NSAIDs, antacids and glucorticosteroids, which may lower blood salicylate concentration during treatment and result in high levels when treatment is stopped.

The effects of diuretics and uricosurics may also be affected by salicylates.

Other anti-platelet drugs

Salicylates may increase risk of bleeding with clopidogrel and ticlopidine.

Leukotriene antagonists

Aspirin may increase plasma concentration of zafirlukast

Mifepristone

Based on theoretical grounds, mifepristone may interact with salicylates.

4.6 Fertility, pregnancy and lactation

Metoclopramide

Pregnancy

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicates no malformative toxicity nor foetotoxicity. Metoclopramide can be used during pregnancy if clinically needed. Due to pharmacological properties (as other neuroleptics), in case of metoclopramide administration at the end of pregnancy, extrapyramidal syndrome in newborns cannot be excluded. Metoclopramide should be avoided at the end of pregnancy. If metoclopramide is used, neonatal monitoring should be undertaken.

Due to pharmacological properties, as with other benzamides, in instances of metoclopramide administration before delivery, extrapyramidal disorders in newborns cannot be excluded.

Breastfeeding

Metoclopramide is excreted in breast milk at low level. Adverse reactions in the breast-fed baby cannot be excluded. Therefore metoclopramide is not recommended during breastfeeding. Discontinuation of metoclopramide in breastfeeding women should be considered.

Acetylsalicylic acid

Pregnancy

Although teratogenic effects of acetylsalicylic acid have been recorded in animals, no such effects have been observed in humans.

No teratogenic effects have been observed with metoclopramide: data on pregnant patients (> 1000) indicate no malformative nor foeto/neonatal toxicity during 1rst trimester of pregnancy. A limited amount of data on pregnant patients (> 300) indicates no neonatal toxicity in other trimesters. Animal studies do not indicate reproductive toxicity.

In the third trimester, the use of prostaglandin synthesis inhibitors such as acetylsalicylic acid may expose the foetus to premature closure of the ductus arteriosus. MigraMax is therefore contra-indicated during the third trimester. Like all drugs avoid use in the first and second trimester unless the physician believes the benefits outweigh the risk.

Breastfeeding

MigraMax is not recommended during lactation because acetylsalicylic acid is excreted in breast milk and adverse reactions in the breast-fed baby cannot be excluded. A decision should be made whether to discontinue breast-feeding or to abstain from Migramax treatment.

4.7 Effects on ability to drive and use machines

MigraMax may cause drowsiness, dizziness, dyskinesia and dystonias which could affect the vision and also interfere with the ability to drive and operate machinery. This effect can be potentiated by CNS depressants or alcohol.

4.8 Undesirable effects

Adverse reactions listed by System Organ Class.

Frequencies are defined using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

System Organ Class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Not known

Methaemoglobinaemia, which could be related to NADH cytochrome b5 reductase deficiency, particularly in neonates (see section 4.4) Sulfhaemoglobinaemia, mainly with concomitant administration of high doses of sulphur-releasing medicinal products, thrombocytopenia, intracranial haemorrhage which may be fatal, especially in the elderly.

Haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency (see section 4.4).

Cardiac disorders

Uncommon

Bradycardia, particularly with intravenous formulation

Not known

Cardiac arrest, occurring shortly after injectable use, and which can be subsequent to bradycardia (see section 4.4); atrioventricular block, sinus arrest particularly with intravenous formulation; electrocardiogram QT prolonged; Torsade de Pointes; transient increase in blood pressure

Endocrine disorders *

Uncommon

Amenorrhoea, hyperprolactinaemia

Rare

Galactorrhoea

Not known

Gynaecomastia

Gastrointestinal disorders

Common

Diarrhoea, flatulence,

gastric irritation with blood loss, nausea, dyspepsia, vomiting and gastric ulceration. The gastrointestinal haemorrhaging is occasionally severe but in most cases blood loss is not significant.

Not known

Oesophagitis, erosive duodenitis, erosive gastritis, esophageal ulceration, perforation, small (jejunum and ileum) and large (colon and rectum) intestinal ulcers, colitis and intestinal perforation.

These reactions may or may not be associated with haemorrhage, and may occur at any dose of acetylsalicyclic acid and in patients with or without warning symptoms or a previous history of serious GI events

General disorders and administration site conditions

Common

Asthenia

Immune system disorders

Uncommon

Hypersensitivity

Very rare

Salicylates may induce hypersensitivity especially in those individuals with asthma or rhinitis, and a history of atopy or nasal polyps. The observed hypersensitivity reactions include anaphylaxis, urticaria and bronchospasm.

Not known

Anaphylactic reaction (including anaphylactic shock particularly with intravenous formulation)

Nervous system disorders

Very common

Somnolence

Common

Extrapyramidal disorders (particularly in children and young adults and/or when the recommended dose is exceeded, even following administration of a single dose of the drug) (see section 4.4), Parkinsonism, Akathisia

Uncommon

Dystonia, dyskinesia, depressed level of consciousness

Rare

Convulsions, especially in epileptic patients

Not known

Tardive dyskinesia which may be persistent, during or after prolonged treatment, particularly in elderly patients (see section 4.4), Neuroleptic malignant syndrome (see section 4.4), restlessness, anxiety

Psychiatric disorders

Common

Depression

Uncommon

Hallucination

Rare

Confusional state

Vascular disorders

Common

Hypotension, particularly with intravenous formulation

Not known

Shock, syncope after injectable use, acute hypertension in patients with phaeochromocytoma (see section 4.3)

Respiratory, thoracic and mediastinal disorders

Not known

Non-cardiogenic pulmonary oedema with chronic use and in the context of a hypersensitivity reaction due to acetylsalicyclic acid

Ear and labyrinth disorders

Not known

Tinnitus

Renal and urinary disorders

Not known

Other reported effects of salicylates include urate kidney stones

Skin and subcutaneous tissue disorders

Not known

Fixed eruption

Hepatobiliary disorders

Not known

Elevation of hepatic enzymes

Liver injury mainly hepatocellular

Chronic hepatitis

* Endocrine disorders during prolonged treatment in relation with hyperprolactinaemia (amenorrhoea, galactorrhoea, gynaecomastia).

The following reactions, sometimes associated, occur more frequently when high doses are used:

• Extrapyramidal symptoms: acute dystonia and dyskinesia, parkinsonian syndrome, akathisia, even following administration of a single dose of the medicinal product, particularly in children and young adults (see section 4.4).

• Drowsiness, decreased level of consciousness, confusion, hallucination.

Aspirin may increase bleeding time, decrease platelet adhesiveness, and in large doses cause hypothrombinaemia. It may cause other blood disorders, including thrombocytopenia, iron deficiency or haemolytic anaemia and rarely agranulocytosis.

4.9 Overdose

In cases of overdose, toxic reactions are mainly ascribable to aspirin.

Salicylate poisoning is usually associated with plasma concentrations >350 mg/L (2.5mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (95.1mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious poisoning.

Acetylsalicylic symptoms

Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases. A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of 4 years. In children aged 4 years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier. Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.

Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.

Non-cardiogenic pulmonary oedema can occur with acute and chronic acetylsalicyclic acid overdose (see section 4.8).

Metoclopramide symptoms

Extrapyramidal disorders, drowsiness, decreased level of consciousness, confusion, hallucination, and cardio-respiratory arrest may occur.

Management

Give activated charcoal if an adult presents within one hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema. Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations > 700 mg/L (5.1 mmol/L), or lower concentrations associated with severe clinical or metabolic features. Patients under 10 years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

Decreased levels of consciousness, confusion, hallucinations resolve after metoclopramide withdrawal.

Treatment for extrapyramidal disorders caused by metoclopramide, whether related or not to overdose, is only symptomatic (benzodiazepines in children and/or anticholinergic anti-parkinsonian medicinal products in adults).

A symptomatic treatment and a continuous monitoring of the cardiovascular and respiratory functions should be carried out according to clinical status.

5. Pharmacological properties
5.1 Pharmacodynamic properties

The pharmacological properties of this product are those of the two active ingredients i.e. an analgesic and an antiemetic.

Acetylsalcyclic acid has analgesic, antipyretic and anti-inflammatory properties. It inhibits prostaglandin synthesis so that the prostaglandin-induced sensitivity of peripheral nerve endings to kinins and other mediators of pain and inflammation are reduced. Acetylsalicylic acid also exerts a powerful inhibition on platelet aggregation by blocking thromboxane A2 synthesis in the platelets.

Metoclopramide is an effective anti-emetic, although its exact mechanism(s) of action is not fully established. It is a cholinergic agonist acting peripherally to enhance the action of acetylcholine at muscarinic synapses and in the CNS by blocking dopamine receptors in the chemoreceptor trigger zone for vomiting.

Local effects include the promotion of gastric emptying and normal peristalsis, impairment of which are a common feature of migraine attacks.

5.2 Pharmacokinetic properties

Lysine acetylsalicylate

Absorption of lysine acetylsalicylate as a solution is rapid in healthy subjects. Lysine acetylsalicylate dissociates into lysine and acetylsalicylic acid which is rapidly hydrolysed to salicylic acid. The plasma peak of acetylsalicylic acid is achieved within 20 minutes.

Plasma salicylates are essentially bound to plasma proteins and are converted to inactive metabolites in the liver. Salicylic acid and its metabolites are excreted via the kidneys. Clearance increases with increasing urinary pH. The elimination half-life of salicylic acid is dose-dependent owing to the saturable nature of salicylic acid conjugation and ranges from as little as 2 hours after a single dose of 500 mg, lengthening to as long as 20 hours in overdosage.

Metoclopramide

The plasma peak of metoclopramide is reached within an average time of 40 minutes following oral administration. Peak plasma concentrations are 32 and 70 g/L for 10 and 20 mg doses.

Bioavailability is 80% following oral administration. Inter-individual variations are related to a 20% first-pass effect. Metoclopramide is rapidly and extensively distributed in tissues. The volume of distribution is 2.2 - 3.4 l/kg. Metoclopramide has a low degree of binding to plasma proteins (30%). The plasma elimination half-life of metoclopramide is 5 - 6 hours. Total clearance is 0.4 - 0.7 l/min.

Metoclopramide is only partially metabolised in humans; urinary excretion occurs essentially as the unchanged and sulphoconjugated compounds (50% of the dose administered).

Renal impairment

The clearance of metoclopramide is reduced by up to 70% in patients with severe renal impairment, while the plasma elimination half-life is increased (approximately 10 hours for a creatinine clearance of 10-50 mL/minute and 15 hours for a creatinine clearance.

Hepatic impairment

In patients with cirrhosis of the liver, an accumulation of metoclopramide has been observed, associated with a 50% reduction in plasma clearance.

Combination

When administered as an oral solution, lysine acetylsalicylate and metoclopramide are rapidly absorbed.

In subjects not suffering from migraine, plasma concentrations of total salicylates, acetylsalicylic acid and metoclopramide do not differ from those recorded following both drugs administered singly.

The elimination half-life of salicylates and metoclopramide is unaffected in subjects suffering from migraine receiving the two drugs in combination compared with normal subjects.

5.3 Preclinical safety data

No data of therapeutic relevance.

6. Pharmaceutical particulars
6.1 List of excipients

Aspartame

Glycine

Lemon flavour (essential oil of lemon absorbed on a maltodextrin substrate)

6.2 Incompatibilities

No known major incompatibilities

6.3 Shelf life

1 year

6.4 Special precautions for storage

Store at or below 25oC

6.5 Nature and contents of container

Pack sizes:

Carton containing 2 sachets

Carton containing 6 sachets

Carton containing 20 sachets

MigraMax is packaged in sachets made of a paper-polyethylene-aluminium complex, containing one unit dose and heat-sealed.

6.6 Special precautions for disposal and other handling

Consult the patient leaflet before use.

Do not use after the stated expiry date on the sachet or carton.

To be taken orally when the powder is completely dissolved.

7. Marketing authorisation holder

Zentiva Pharma UK Limited

12 New Fetter Lane

London

EC4A 1JP

United Kingdom

8. Marketing authorisation number(s)

PL 17780/0552

9. Date of first authorisation/renewal of the authorisation

16 March 2011

10. Date of revision of the text

15/11/2021